Although fetal alcohol spectrum disorders (FASD) is the leading known cause of mental retardation and produces cognitive and behavioral abnormalities, the underlying mechanisms of neuropathogenesis are poorly defined. We have identified microglia as targets of ethanol pathogenesis in the developing CNS, with relevant translation to FASD. Using our neonatal rodent model of FASD, we discovered that ethanol causes microglial death. Surviving microglia express an activated phenotype, evident with morphological change and expression of antigenic activation markers. We identified signaling pathways that are dysregulated by ethanol and found that ethanol suppresses expression of peroxisome proliferator-activated receptor-3 (PPAR3), whose activity is anti-inflammatory and neuroprotective. Particularly intriguing, PPAR3 agonist treatment prevents microencephaly, growth retardation, microglial and neuronal death, and inflammatory pathology. We hypothesize that ethanol suppression of PPAR3 signaling contributes to cell death and, further, that PPAR3 agonists protect against ethanol through a PPAR3 receptor-dependent mechanism. This will be investigated using our rat model of FASD and co-cultures of microglia and neurons. (1) We will determine the mechanism of PPAR3 agonist protection against ethanol. These studies will determine if PPAR3 agonists modulate microglial and neuronal survival through receptor-dependent or receptor-independent mechanisms. The contribution of retinoid X receptor-1 (RXR1) will also be evaluated. (2) The ability of several FDA-approved PPAR3 and RXR1 agonists to prevent ethanol-induced death of neurons and microglia and/or prevent neuroinflammatory pathology will be determined and relative efficacy established. The ability of agonists to evoke change in targeted inflammatory molecules will be probed to identify not only the mechanism of agonist protection but uncover new candidates for pharmacological and therapeutic investigation. The results of the proposed investigation will be significant because they will bring new understanding of FASD mechanisms and provide new opportunities for therapeutic intervention in the cell death and inflammatory pathology caused by ethanol. Innovative application of the preclinical rat model of FASD to determine the mechanism and efficacy of novel treatments to prevent ethanol neuropathology holds promise for the future of FASD research. . PUBLIC HEALTH RELEVANCE: Although fetal alcohol spectrum disorders (FASD) is the leading known cause of mental retardation and produces cognitive and behavioral abnormalities. We have found that ethanol causes microglial death and that surviving microglia express an activated, pro-inflammatory phenotype. We identified signaling pathways that are dysregulated by ethanol and found that ethanol suppresses the anti-inflammatory and neuroprotective PPAR3 pathways. Particularly intriguing, PPAR3 agonists can block ethanol neuropathogenesis. This study will determine the mechanism of PPAR3 agonist protection against ethanol. In addition, the ability of FDA- approved PPAR3 and RXR1 agonists to prevent ethanol-induced death of neurons and microglia and/or prevent neuroinflammatory pathology will be determined and relative efficacy established. The results of the proposed investigation will be innovative and significant because they will bring new understanding of FASD mechanisms and provide new opportunities for therapeutic intervention in the cell death and inflammatory pathology caused by ethanol.